Identification of a novel haplotype of the human catechol-O-methyltransferase gene.
Identification of a novel haplotype of the human catechol-O-methyltransferase gene.
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DOI：
10.1097/fpc.0b013e32830fbde4
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发表时间：
2009-01
影响因子：
2.6
通讯作者：
Zhu BT
中科院分区：
文献类型：
--
作者：
Bai HW;Zhu BT
Human catechol-O-methyltransferase (COMT; EC 2.1.1.6) catalyzes the transfer of the methyl group to a variety of endogenous and exogenous catechol substrates using S-adenosyl-L-methionine as the methyl donor. This enzymatic O-methylation plays an important role in the inactivation of biologically-active and toxic catechols. A number of studies in recent years have sought to characterize the polymorphism of human COMTs, and also to determine the catalytic activity of polymorphic enzymes. We report here the identification of a new mutant form of the human COMT gene with triplet point mutations, which encodes the D51G/S60F/K162R mutant of the soluble COMT and the D101G/S110F/K212R mutant of the membrane-bound COMT. Kinetic analysis showed that these new mutant COMTs had essentially the same kinetic characteristics and catalytic activity as the wild-type COMTs for the O-methylation of 2-hydroxyestradiol and 4-hydroxyestradiol in vitro, but the mutants have a significantly reduced thermostability at 37°C. In addition, the mutant enzymes have different binding affinities for S-adenosyl-L-methionine compared with the wild-type COMTs. In agreement with our biochemical observations, molecular modeling studies also showed that the mutant human COMT proteins shared nearly the same overall structures as the wild-type proteins. The binding energy values of the mutant COMTs in complex with catechol estrogen substrates were similar to those of the wild-type COMTs bound with the same substrates.
